The aim of this Program is the induction and maintenance of immune tolerance to organ transplants. In Projects 1 and 2, the mechanisms underlying the immuno-suppressive effects of synthetic peptides corresponding to structural regions of HLA molecules will be investigated. The studies proposed in Project 3 will develop retroviral vectors for the in vivo delivery of these peptides in mammalian cells and evaluate their efficacy in animal models of allograft rejection. In aim 1, a series of retroviral vectors with inducible and constitutive promoters will be created. These vectors will allow the peptides to be expressed in intracellular or secreted forms. In aim 2, the vectors created in aim 1 will be used to infect mammalian cells in vitro. A series of molecular tags will be used to determine the intra- and extra-cellular fate of the peptides. The effects of expressed peptides on both lysis by cytotoxic T lymphocytes and the cell cycle will be determined. In aim 3, the retroviral vectors will be used as therapy in three animal models: heterotopic heart transplantation, graft versus host disease, and diabetes mellitus in NOD mice. This Project interacts with both Projects 1 and 2 and provides the basis for the eventual use of retroviral constructs for the development of immune tolerance in humans.